TIAM1 acts as an actin organization regulator to control adipose-derived pericyte cell fate.

Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose and periosteal-derived pericyte microarrays, we identified TIAM1 as a key regulator of cell morphology and differentiation decisions. TIAM1 represents a tissue-specific determinant between predispositions for adipocytic versus osteoblastic differentiation in human pericytes. TIAM1 overexpression promotes an adipogenic phenotype, whereas its downregulation amplifies osteogenic differentiation. These results were replicated in vivo xenograft animal model, in which TIAM1 misexpression altered bone or adipose tissue generation in an intramuscular xenograft animal model. Changes in pericyte differentiation potential induced by TIAM1 misexpression correlated with actin organization and altered cytoskeletal morphology. Small molecule inhibitors of either Rac1 or RhoA/ROCK signaling reversed TIAM1-induced morphology and differentiation in pericytes. Finally, pericytes within calcified vessels demonstrated decreased TIAM1 expression in the diseased area compared to the healthy tissue. In summary, our results demonstrate that TIAM1 regulates the cellular morphology and differentiation potential of human pericytes, representing a molecular switch between osteogenic and adipogenic cell fates.